|Year : 2015 | Volume
| Issue : 2 | Page : 121-122
Repurposing of bacillus Calmette-Guerin (BCG): Prevention, remission or cure in Type 1 diabetes?
Om Prakash Gupta
Department of Medicine, MGIMS, Sevagram, Wardha, Maharashtra, India
|Date of Web Publication||2-Sep-2015|
Om Prakash Gupta
MGIMS, Sevagram, Wardha, Maharashtra
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Gupta OP. Repurposing of bacillus Calmette-Guerin (BCG): Prevention, remission or cure in Type 1 diabetes?. J Mahatma Gandhi Inst Med Sci 2015;20:121-2
|How to cite this URL:|
Gupta OP. Repurposing of bacillus Calmette-Guerin (BCG): Prevention, remission or cure in Type 1 diabetes?. J Mahatma Gandhi Inst Med Sci [serial online] 2015 [cited 2019 Jan 24];20:121-2. Available from: http://www.jmgims.co.in/text.asp?2015/20/2/121/164224
"This is an exciting time to try to bring a cheap, generic drug forward to people with longstanding Type 1 diabetes."
- Dr. Denis Faustman
Prevalence of diabetes is increasing all over world, from 171 million in the year 2000; it is likely to be 366 million in 2030. The prevalence in India has rapidly increased both in rural and urban areas, and is projected to be 79.4 million in 2030 from 31.7 million in 2000, majority of them being Type 2 diabetes (about 85%).  India has been named by the World Health Organization as the "capital of diabetes." For decades scientists are attempting to find out a solution for daily insulin injections in case of Type 1 diabetes. The embryonic stem cell research is the one such endeavor. Recent reports have shown that a large quantity of insulin producing cells can be made and within few years it will be possible to implant these cells subcutaneously, making daily insulin injections almost redundant.  Two other molecules are under different stages of trials; "Alefacept" which depletes CD4 and CD8 cells; the central memory cells, as well as effector memory cells and preserve the regulatory T-cells.  The other one is immunosuppressive monoclonal antibody "leptizumab (anti-CD3 antibody)" which is found to be effective and some patients have continued to show benefit, with only a moderate need of insulin.  Long-term efficacy without adverse effects and low costs are always the considerations when the treatment is to be continued lifelong.
Bacillus Calmette-Guerin (BCG - a live attenuated vaccine) vaccination has been used since 1921 to prevent tuberculosis (TB), though studies have shown its efficacy to be 0-80%. However, it has been evident in the literature that it provides protection against military TB and TB meningitis. The 15 years Indian Council of Medical Research study concluded that, in the population with high infection rate and high nonspecific sensitivity, BCG offers no protection against adult form of pulmonary TB; and a very low level protection (27%; 95% confidence interval 8-50%) in children.  It has been found to have some degree protection against leprosy as evident from the recent reports. 
Since the late 1970s, studies have demonstrated that that instillation of BCG into the bladder is an effective form of immunotherapy in the superficial form of bladder cancer. The immune system of the body fails to recognize the cancerous cells as foreign, and they continue to multiply. Though the mechanism of action of BCG is not well understood in this context, it is thought to be an immune response against BCG surface antigen cross reacting with putative bladder tumor antigens. In bladder macrophages, it induces similar immunologic and histological reaction as in TB. It enters the bladder cancer cells, breaking the cellular proteins. This induces cytokines and cell-to-cell cytotoxicity destroying the cancer cells. Studies have consistently shown that BCG treatment can eradicate this cancer in 70% of patients, in whom the tumor burden is small. However, it is imperative that direct contact with the tumor should occur, and the dose should be adequate to incite a reaction. To prevent cancer recurrence, long-term maintenance therapy following the induction phase is necessary. 
BCG has also been used in other cancers, e.g., as an adjuvant to surgery in lung cancer,  oral and maxillofacial melanoma  breast, and colorectal carcinoma. 
Recently, Dr. Denis Faustman carried out studies at Massachusetts General Hospital Lab in Type 1 diabetic mice, and found that BCG eliminates T-cell which is responsible for the destruction of β-cells of pancreas and thus, permanently reverses Type 1 diabetes. Encouraged by these results, the first human study was launched in 2008 - BCG Human Clinical Trial Program (Phase 1 double blind place controlled trial) approved by Food and drug administration [FDA]USA, which showed that BCG is a promising treatment for Type 1 diabetes. It has been reported that BCG raises the levels of tumor necrosis factor [a signaling protein involved in the body's immune responses] which in turn eliminate the T-cell responsible for the destruction of β-cells. Also, the number of regulatory T-cells increased, and insulin production was restored even in those who had diabetes for about 15 years. It does not require long-term immunosuppression or stem cell transplantation. Safety studies have been carried out, and BCG is found to be safe (no serious adverse reaction noted) and is inexpensive. 
It is presumed that by the time one has overt Type 1 diabetes; all the insulin producing cells (β-cell of the pancreas) are destroyed. But it is not so, some cells are preserved for many years, which can regenerate. In Phase 1 trial, two injections of BCG spaced 4 weeks apart were given which resulted in the elimination of diabetes producing T-cells, preserving and regenerating β-cells, and increasing insulin secretion confirmed by C-peptide measurements. However, in Phase 1 trial the effect lasted for 1-week only. It means the patients would have to receive BCG vaccination for life but much less frequently than the insulin. Recently, FDA (USA) has permitted phase 2 trial which will look at what doses of BCG are needed to make this a functional and sustained Type 1 diabetes therapy, and how frequently it would need to be given. The goal is to reverse the advanced diabetes not just temporarily halt the new disease. 
The day is not far when curing Type 1 diabetes may finally be within reach!!
| References|| |
WHO. WHO Position Paper on BCG Vaccination (PDF). Vol. 79. Geneva: WHO; 2004. p. 25-40.
Kaveeshwar SA, Cornwall J. The current state of diabetes mellitus in India. Australas Med J 2014;7:45-8.
Merle CS, Cunha SS, Rodrigues LC. BCG vaccination and leprosy protection: Review of current evidence and status of BCG in leprosy control. Expert Rev Vaccines 2010;9:209-22.
Available from: https://www.ncbi.nlm.nih.gov/pubmed/16538310. [Last accessed on 2015 Jul 23].
Available from: https://www.ncbi.nlm.nih.gov/pubmed/16026248. [Last accessed on 2015 Jul 23].